Ajaz S. Hussain, Ph.D. and Vadim Gurvich, Ph.D.

The National Institute of Pharmaceutical Technology & Education, Inc.

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Excipients: IFPAC 2017Chair: Brian Carlin

Background: NIPTE 2016

NIPTE resurgence, passion, and expansion (new members)

Expansion of stakeholders beyond US FDA; while maintaining commitment to FDA collaboration

Reflection on roadblocks and strategies for roadmap 2017

This presentation co-author:

Dr. Vadim Gurvich, Executive Director

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Presenter (Ajaz): Declaring my interests

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Insight Advice & Solutions LLC

Advisory and Consulting Practice

Complex Generics, Biosimilars & Orphan Drugs

Advisory Boards: Several Companies

When requested:

Systems approach - CGMP Remediation (strategy)

Culture of Pharmaceutical Quality Training

with Emphasis on Data Integrity

President

Share my understanding of challenges

in the assurance of "Pharmaceutical Quality”

Strategic planning and NIPTE advocacy.

Programing and other executive functions.

Legislative recognition: 2006 to 2016FDA leadership, FDA Grants,…..

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2006: Federal investments in a major pharmaceutical technology and education initiative led by the Food and Drug Administration in collaboration with university research partners will produce multiple benefits in health care quality and access.2016: FDA may award grants to institutions of higher education and nonprofit organizations for the purpose of studying and recommending improvements to the process of continuous manufacturing of drugs and biological products and similar innovative monitoring and control techniques.

Organizational Maturity, Epistemology and Continuous Improvement Transformation: Biotech “Tipping Point”

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Martin VanTrieste, R. Ph. Improving the Quality of Investigations. PIA Meeting – June 21, 2012

3 September 2003

Solid Dosage Form Manufacturing: “Tipping Point” not feasible without an “Angle of Repose”

• Certificate of Analysis • Uncertainty in solid-state material attributes

• Research laboratory measurement systems• Life-cycle stability and reproducibility in QC?

• Fixed equipment and process parameters• Committed in submissions, difficult to change post

approval; why bother finding the real cause?

• Uncertainty in the stability and capability of measurements and manufacturing process• Raises questions on adequacy of sampling and

obstructs risk-based decisions

• Globalization – variable empowerment/oversight• “FDA Approved” and “Validated”; frames the

mindset and provides reasons to rationalization

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Repeating deviations and errors & ineffective investigations point to cognitive biases and risk of irrational behaviors

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600 days

GXPs & Adult Human Development: The Subjective Dimension [my learning & focus]

An ancient Indian board game: Snakes & Ladder (in the USA: Chutes and

Ladder)

An ancient Indian story: Elephant in the Dark (in

the USA: Six Blind Men & the Elephant)

Integrating: “Orders of Consciousness” (Prof.

Robert Kegan) & “Thinking, Fast and Slow”

(Nobel Laureate Prof. Kahneman)

A journey – “I know it when I see it” to “I can

see clearly now”

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Paradigm, Ontology, Epistemology, Methodology, Methods

“Angle of Repose”: Adaptive learning challenges

Solid Oral Dosage Form Manufacturing

At a Tipping Point

• NDA 26038; Orkambi®, Vertex Pharmaceuticals. 25 June 2015

• Post-approval change: NDA 021976 Prezista® , Janssen. 12 April 2016 (Continuous manufacturing with RTRT)

Progress and set-backs

• Several, ….others (new drugs); generics faced OGD push-back

• 2006 MSD/Merck

The Beginning

• 2004-2005 Sanofi-Aventis Comparability Protocol (FDA Approved - Not Implemented)

• (Late 1990’s: Medical Gas; Air Separation Units)

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Angle of Repose & Tipping Point From “Don’t use or Don’t tell”* to problem-solving mindset,……

PAT-Continuous Manufacturing – RTRT platforms for rapid

product development, control strategy, and Design Space

• Multiple companies and Schools passionately perusing this opportunity with regulatory encouragement and acknowledgment of its potential for higher level of assurance

• Enforcement of Continued Process Verification (PV 2011) now becoming apparent in the USA; adds an emphasis on statistical confidence and process stability and capability

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1

2

3

From: Martin Warman, Kelly Swinney and Justin Pritchard. PAT for In Process Control (IPC) and Real Time Release Testing (RTRT) in Continuous Manufacturing. 7th Pharmaceutical Technology Conference on Continuous Manufacturing, Japan (December 2015)

http://www.fda.gov/ohrms/dockets/ac/02/briefing/3841B1_05_PFIZER.PDF ; FDA Science Board 16 November 2001

Angle of Repose to Tipping Point: Journey needs to now go from extraordinary to normal, easy and rewarding

Technical Learning

• Control strategies (with “new” measurement systems)

• Engineering skills

• Statistics (Chemometrics)

Adaptive Learning

• Culture/Mindset change: reactive to proactive

• Cross-functional collaboration

• Systems thinking, understanding effective QMS, and change management system

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Angle of Repose Tipping PointSufficient to achieve?

Law of the Few, the Stickiness Factor and

the Power of Context

Make the journey normal, easy and rewarding

Societal need (e.g., FDASIA) for confidence in [our] assurance of quality

• Confident assurance of quality across a global supply chain; risk ranking

• Recognition that early detection of issues necessary; effective investigations

• Delay insp. = adulteration; explicit assurance of data integrity

Increased appreciation of PAT-QbD-Lifecycle

Approach to Validation needed for effective QMS

• Operational inefficiency and an apparent inability to improve after regulatory approval can have many consequences

• Outsourcing without an objective assessment of QMS effectiveness is not a solution

PAT-Continuous Manufacturing – RTRT

platforms for rapid product development, control

strategy, and Design Space

• Multiple companies and Engineering & Pharmacy Schools, a critical mass (?), passionately perusing this opportunity with regulatory encouragement and acknowledgment of its potential for higher level of assurance

• Enforcement of Continued Process Verification (PV 2011) now becoming apparent in the USA; adds an emphasis on statistical confidence and process stability and capability

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Today NIPTE’s mission cannot be clearer and its resolve strongerThe strategic themes identified in 2016 are very relevant to address several roadblocks in the progress of NIPTE

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Roadblocks to the “+”

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• NIPTE = Integrative + Adaptive + Centralized

• What is NIPTE (centralized)? What it should standardize?

2016 Strategic Themes

1. Team Science2. Centers of Excellence3. Certification of Education & New Prior Knowledge

Roadmap 2017 How to…?

With 2020 Vision?

Roadmap 2017: Road mapping process

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Team science, Centers of Excellence & Certification

• NIPTE Roadmap 2017 steps towards becoming the 3rd leg of the stool starting 2020

• [Six ways President Trump can create a tipping point for a renaissance of pharmaceutical manufacturing in the USA ]

-----------------------------------------Currently Outside NIPTE------------------------------------------------------

• USP & C-SOPS Roadmap of Transforming Pharmaceutical Manufacturing from Batch to Continuous (not part of NIPTE; Pro bono advisory support to USP)

------------------------------------------Ajaz’s Advisory & Consulting Practice -----------------------------------

• Note for Disclosure & Transparency: Important elements of my consulting practice:• Making Quality by Design normal easy and rewarding; cheating-by-design not profitable• Advisor CONTINUUS Pharmaceuticals (recipient of $4.4 M Contract with US FDA)

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Centralize and standardizeHow to…?

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Instill/practice

— Key message to all: You are NIPTE & NIPTE is You

— Support Individualistic/Adaptive Goals and encourage/facilitate/recognize Collaborative/Integrative practices and contributions

— Adopt NCI Team Science Toolkit

Establish Charter, Process, & Leaders

— NIPTE “Think Tanks” to strengthen the Voice of NIPTE

— Senior Faculty led Center that work in their particular areas of interest (e.g., Pediatric Formulation)

— Governing Charter and process for “NIPTE Brand Endorsement”

Develop, Evaluate, Scale-up, & Execute

— Plan/focus on success of Sun-Pharma Program

— NIPTE QbD Education Curricula and Certification

— New Prior Knowledge: New, Generic & Biosimilar applications

Team Science

2020 Vision

NIPTE Certification

Centers of Excellence

3rd leg of the stool?

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User fee commitments.

“fire-fighting” to minimize impact of (fewer) failures

New policies, practices & staff

Research priorities

Why NIPTE?

What will NIPTE contribute?

How will NIPTE contribute?

Roadmap 2017

The ‘Third-leg of the stool”?

Push for faster approvals

Pressures to reduce price of medicines

Reduce regulatory burden

Revitalize US manufacturing

Pharmaceutical Technology Research & Education

Needs of the Nation

FDANIPTE: 2020?Macro-

environment

Summary & Next Steps

• NIPTE Roadmap 2017

• NIPTE Advocacy

• Expanding stakeholders and collaborations

• We celebrate successes of pharmaceutical technology!

• You are NIPTE and NIPTE is you!

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